Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial

Andrew S Bomback; David Kavanagh; Marina Vivarelli; Matthias Meier; Yaqin Wang; Nicholas J A Webb; Angelo J Trapani; Richard J H Smith

doi:10.1016/j.ekir.2022.07.004

Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial

Kidney Int Rep. 2022 Aug 2;7(10):2150-2159. doi: 10.1016/j.ekir.2022.07.004. eCollection 2022 Oct.

Authors

Andrew S Bomback¹, David Kavanagh^{2

3}, Marina Vivarelli⁴, Matthias Meier⁵, Yaqin Wang⁶, Nicholas J A Webb⁵, Angelo J Trapani⁶, Richard J H Smith⁷

Affiliations

¹ Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, USA.
² Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
³ National Renal Complement Therapeutics Center, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
⁴ Division of Nephrology, Department of Pediatric Subspecialties, IRCCS Ospedale Pediatrico Bambino Gesu, Rome, Italy.
⁵ Novartis Pharmaceutical AG, Basel, Switzerland.
⁶ Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
⁷ Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, USA.

Abstract

Introduction: Complement 3 glomerulopathy (C3G) is a rare kidney disease characterized by dysregulation of the alternative pathway (AP) of the complement system. About 50% of patients with C3G progress to kidney failure within 10 years of diagnosis. Currently, there are no approved therapeutic agents for C3G. Iptacopan is an oral, first-in-class, potent, and selective inhibitor of factor B, a key component of the AP. In a Phase II study, treatment with iptacopan was associated with a reduction in proteinuria and C3 deposit scores in C3G patients with native and transplanted kidneys, respectively.

Methods: APPEAR-C3G (NCT04817618) is a randomized, double-blind, and placebo-controlled Phase III study to evaluate the efficacy and safety of iptacopan in C3G patients, enrolling 68 adults with biopsy-confirmed C3G, reduced C3 (<77 mg/dl), proteinuria ≥1.0 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m². All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplantation, progressive crescentic glomerulonephritis (GN), monoclonal gammopathy of undetermined significance, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg twice daily for all patients for 6 months. The primary objective is to evaluate the efficacy of iptacopan versus placebo on proteinuria reduction urine protein:creatinine ratio (UPCR) (24 h urine). Key secondary endpoints will assess kidney function measured by eGFR, histological disease total activity score, and fatigue.

Conclusion: This study aims to demonstrate the clinical benefits of AP inhibition with iptacopan in C3G.

Keywords: C3G; LNP023; alternative pathway; clinical trials; complement system; factor B; iptacopan.